Down syndrome (DS, trisomy 21) is the most common genetic cause of intellectual disability but the neuroanatomical abnormalities that contribute to specific cognitive deficits have not been well defined. Histopathological observations have consistently implicated reduced interneuron number as a major defect in the DS cerebral cortex. Mouse and human data indicate that interneuron development is faulty in DS and warrant further investigation in human. To better understand how mistakes in interneuron development may underlie intellectual disability in DS, we propose to test the hypothesis that the development of human trisomy 21 (Ts21) interneuron progenitors is impaired. We will develop an in vitro paradigm that uses human induced pluripotent stem cells to model both spatial and temporal aspects of human interneuron progenitor development. Using this system, we will determine whether Ts21 iPSC-derived interneuron progenitors have defects in interneuron generation that may lead to the generation of fewer interneurons in DS brain.